MicroRNAs (miRs) have emerged as major regulators of the protein content of a cell. In the most part, miRs negatively regulate target mRNA expression, with sets of miRs predicted to regulate certain signaling pathways. The miR expression profile of endobronchial brushings is altered in people with cystic fibrosis (CF) compared to those without CF. How this impacts on CF has important implications for our growing understanding of the pathophysiology of CF lung disease and the development of new therapeutics to treat its pulmonary manifestations. Herein we discuss the potential consequences of altered miR expression in CF airway epithelium particularly with respect to cystic fibrosis transmembrane conductance regulator (CFTR) expression, innate immunity and toll-like receptor signalling and explore how best to exploit these changes for therapeutic benefit.
References
[1]
Rowe, S.M.; Miller, S.; Sorscher, E.J. Cystic fibrosis. N. Engl. J. Med.？2005, 352, 1992–2001, doi:10.1056/NEJMra043184. 15888700
[2]
Lommatzsch, S.T.; Aris, R. Genetics of cystic fibrosis. Semin. Respir. Crit. Care Med.？2009, 30, 531–538, doi:10.1055/s-0029-1238911.
[3]
Greene, C.M. How can we target pulmonary inflammation in cystic fibrosis? Open Respir. Med. J.？2010, 4, 18–19. 20448813
[4]
Walsh, D.E.; Greene, C.M.; Carroll, T.P.; Taggart, C.C.; Gallagher, P.M.; O'Neill, S.J.; McElvaney, N.G. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J. Biol. Chem.？2001, 276, 35494–35499, doi:10.1074/jbc.M103543200. 11461907
Bergin, D.A.; Greene, C.M.; Sterchi, E.E.; Kenna, C.; Geraghty, P.; Belaaouaj, A.; Taggart, C.C.; O'Neill, S.J.; McElvaney, N.G. Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. J. Biol. Chem.？2008, 283, 31736–31744, doi:10.1074/jbc.M803732200. 18772136
[7]
Chotirmall, S.H.; Greene, C.M.; Oglesby, I.K.; Thomas, W.; O'Neill, S.J.; Harvey, B.J.; McElvaney, N.G. 17beta-estradiol inhibits IL-8 in cystic fibrosis by up-regulating secretory leucoprotease inhibitor. Am. J. Respir. Crit. Care Med.？2010, 182, 62–72, doi:10.1164/rccm.201001-0053OC.
[8]
Cosgrove, S.; Chotirmall, S.H.; Greene, C.M.; McElvaney, N.G. Pulmonary proteases in the cystic fibrosis lung induce interleukin-8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/toll-like receptor pathway. J. Biol. Chem.？2011, 286, 7692–7704, doi:10.1074/jbc.M110.183863. 21193404
[9]
Hassan, T.; McKiernan, P.J.; McElvaney, N.G.; Cryan, S.A.; Greene, C.M. Therapeutic modulation of miRNA for the treatment of proinflammatory lung diseases. Expert Rev. Anti Infect. Ther.？2012, 10, 359–368, doi:10.1586/eri.11.175.
[10]
Oglesby, I.K.; Bray, I.M.; Chotirmall, S.H.; Stallings, R.L.; O'Neill, S.J.; McElvaney, N.G.; Greene, C.M. miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression. J. Immunol.？2010, 184, 1702–1709, doi:10.4049/jimmunol.0902669. 20083669
[11]
Bhattacharyya, S.; Balakathiresan, N.S.; Dalgard, C.; Gutti, U.; Armistead, D.; Jozwik, C.; Srivastava, M.; Pollard, H.B.; Biswas, R. Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8. J. Biol. Chem.？2011, 286, 11604–11615, doi:10.1074/jbc.M110.198390. 21282106
[12]
Bazett, M.; Paun, A.; Haston, C.K. MicroRNA profiling of cystic fibrosis intestinal disease in mice. Mol. Genet. Metab.？2011, 103, 38–43, doi:10.1016/j.ymgme.2011.01.012.
[13]
Gillen, A.E.; Gosalia, N.; Leir, S.H.; Harris, A. MicroRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene. Biochem. J.？2011, 438, 25–32, doi:10.1042/BJ20110672. 21689072
[14]
Megiorni, F.; Cialfi, S.; Dominici, C.; Quattrucci, S.; Pizzuti, A. Synergistic post-transcriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by miR-101 and miR-494 specific binding. PLoS One？2011, 6, e26601, doi:10.1371/journal.pone.0026601. 22028919
[15]
Ramachandran, S.; Karp, P.H.; Jiang, P.; Ostedgaard, L.S.; Walz, A.E.; Fisher, J.T.; Keshavjee, S.; Lennox, K.A.; Jacobi, A.M.; Rose, S.D.; et al. A microRNA network regulates expression and biosynthesis of wild-type and deltaF508 mutant cystic fibrosis transmembrane conductance regulator. Proc. Natl. Acad. Sci. USA？2012, 109, 13362–13367, doi:10.1073/pnas.1210906109. 22853952
[16]
Hassan, F.; Nuovo, G.J.; Crawford, M.; Boyaka, P.N.; Kirkby, S.; Nana-Sinkam, S.P.; Cormet-Boyaka, E. miR-101 and miR-144 regulate the expression of the CFTR chloride channel in the lung. PLoS One？2012, 7, e50837, doi:10.1371/journal.pone.0050837. 23226399
[17]
Oglesby, I.K.; Chotirmall, S.H.; McElvaney, N.G.; Greene, C.M. Regulation of CFTR by microRNA-145, -223 and -494 is altered in ΔF508 cystic fibrosis airway epithelium. J. Immunol.？2013. Accepted for Publication on 23 January 2013.
[18]
Hartl, D.; Gaggar, A.; Bruscia, E.; Hector, A.; Marcos, V.; Jung, A.; Greene, C.; McElvaney, G.; Mall, M.; Doring, G. Innate immunity in cystic fibrosis lung disease. J. Cyst. Fibros.？2012, 11, 363–382, doi:10.1016/j.jcf.2012.07.003.
Hu, N.; Zhang, J.; Cui, W.; Kong, G.; Zhang, S.; Yue, L.; Bai, X.; Zhang, Z.; Zhang, W.; Zhang, X.; et al. miR-520b regulates migration of breast cancer cells by targeting hepatitis B x-interacting protein and interleukin-8. J. Biol. Chem.？2011, 286, 13714–13722, doi:10.1074/jbc.M110.204131. 21343296
[29]
Yu, Z.; Willmarth, N.E.; Zhou, J.; Katiyar, S.; Wang, M.; Liu, Y.; McCue, P.A.; Quong, A.A.; Lisanti, M.P.; Pestell, R.G. MicroRNA-17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc. Natl. Acad. Sci. USA？2010, 107, 8231–8236, doi:10.1073/pnas.1002080107. 20406904
[30]
Gambari, R.; Borgatti, M.; Bezzerri, V.; Nicolis, E.; Lampronti, I.; Dechecchi, M.C.; Mancini, I.; Tamanini, A.; Cabrini, G. Decoy oligodeoxyribonucleotides and peptide nucleic acids-DNA chimeras targeting nuclear factor kappa B: Inhibition of IL-8 gene expression in cystic fibrosis cells infected with Pseudomonas aeruginosa. Biochem. Pharmacol.？2010, 80, 1887–1894, doi:10.1016/j.bcp.2010.06.047. 20615393
[31]
Nicolis, E.; Lampronti, I.; Dechecchi, M.C.; Borgatti, M.; Tamanini, A.; Bezzerri, V.; Bianchi, N.; Mazzon, M.; Mancini, I.; Giri, M.G.; et al. Modulation of expression of IL-8 gene in bronchial epithelial cells by 5-methoxypsoralen. Int. Immunopharmacol.？2009, 9, 1411–1422, doi:10.1016/j.intimp.2009.08.013. 19720161
[32]
Cigana, C.; Nicolis, E.; Pasetto, M.; Assael, B.M.; Melotti, P. Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Biochem. Biophys. Res. Commun.？2006, 350, 977–982, doi:10.1016/j.bbrc.2006.09.132.
[33]
Raia, V.; Maiuri, L.; Ciacci, C.; Ricciardelli, I.; Vacca, L.; Auricchio, S.; Cimmino, M.; Cavaliere, M.; Nardone, M.; Cesaro, A.; et al. Inhibition of p38 mitogen activated protein kinase controls airway inflammation in cystic fibrosis. Thorax？2005, 60, 773–780, doi:10.1136/thx.2005.042564.
Lee, E.; Lindo, T.; Jackson, N.; Meng-Choong, L.; Reynolds, P.; Hill, A.; Haswell, M.; Jackson, S.; Kilfeather, S. Reversal of human neutrophil survival by leukotriene B(4) receptor blockade and 5-lipoxygenase and 5-lipoxygenase activating protein inhibitors. Am. J. Respir. Crit. Care Med.？1999, 160, 2079–2085, doi:10.1164/ajrccm.160.6.9903136. 10588632
[37]
Esau, C.C.; Monia, B.P. Therapeutic potential for microRNAs. Adv. Drug Deliv. Rev.？2007, 59, 101–114, doi:10.1016/j.addr.2007.03.007.
[38]
Soifer, H.S.; Rossi, J.J.; Saetrom, P. MicroRNAs in disease and potential therapeutic applications. Mol. Ther.？2007, 15, 2070–2079, doi:10.1038/sj.mt.6300311.
[39]
Sivadas, N.; Cryan, S.A. Inhalable, bioresponsive microparticles for targeted drug delivery in the lungs. J. Pharm. Pharmacol.？2011, 63, 369–375, doi:10.1111/j.2042-7158.2010.01234.x.
[40]
Patton, J.S.; Byron, P.R. Inhaling medicines: Delivering drugs to the body through the lungs. Nat. Rev. Drug Discov.？2007, 6, 67–74, doi:10.1038/nrd2153.
[41]
Clift, M.J.; Gehr, P.; Rothen-Rutishauser, B. Nanotoxicology: A perspective and discussion of whether or not in vitro testing is a valid alternative. Arch. Toxicol.？2011, 85, 723–731, doi:10.1007/s00204-010-0560-6.
